Inorganic Polyphosphate in Mammals: Mechanisms, Maladies, and Moving Forward.

Inorganic polyphosphate is highly conserved, critical, yet poorly understood polymer that regulates diverse cellular functions in mammals. Its importance is well established in coagulation, inflammation, mitochondrial function, and stress responses, though the molecular mechanisms for these effects remain only partly understood. Fundamental questions also persist regarding its physiological concentration, chain-length distributions, and the mechanisms that regulate its behavior in specific cellular compartments. Progress is limited by the absence of a known mammalian polyphosphate-synthesizing enzyme. Despite this, recent studies have broadened the scope of polyphosphate biology, suggesting roles in protein phase separation, ATP-independent chaperone activity, metabolic regulation, and intracellular signaling. Polyphosphate modulates the mitochondrial permeability transition pore through calcium-dependent regulation and activates factor XII in coagulation. Findings have also introduced potential connections between polyphosphate and processes such as neurodegeneration, cancer, and tissue regeneration. Despite this expanding landscape, many biological effects remain difficult to interpret due to incomplete mapping of protein targets and longstanding technical limitations in detecting and quantifying polyP. This review integrates molecular protein-interaction mechanisms with compartment-specific functions and disease physiology, providing a clearer mechanistic framework while identifying key conceptual and methodological gaps and outlining priorities for advancing polyphosphate research in mammalian systems.